Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection in infants and young children. In addition, RSV causes serious disease in elderly and immune compromised individuals. Immunization against RSV is associated with enhanced disease and pulmonary eosinophilia following natural infection that is thought to be caused by an exuberant memory CD4 Th2 response. As a consequence, there is currently no approved RSV vaccine and detailed studies directed towards prevention of vaccine-associated disease are a necessary first step in the development of a safe and effective vaccine. The BALB/c mouse model of RSV infection faithfully mimics the human respiratory disease including the development of extensive lung inflammation and injury, pulmonary eosinophilia, and enhanced disease in mice previously immunized with either formalin inactivated (FI)-RSV or a recombinant vaccinia virus (vv) that expresses the attachment (G) glycoprotein. Memory CD4 T cells secreting Th2 cytokines are necessary for this response because their depletion eliminates eosinophilia. Recent studies have demonstrated that RSV- specific CD8 T cells can inhibit Th2-mediated pulmonary eosinophilia in vvG-primed mice by as yet unknown mechanisms. By taking advantage of our ability to track RSV G-specific CD4 T cells, we will determine the mechanism of memory CD8 T cell inhibition of RSV G-induced pulmonary eosinophilia. Importantly, recent work has provided evidence that vvG and FI-RSV immunization may induce RSV vaccine-enhanced disease via unique mechanisms. Therefore, we will also ascertain if RSV-specific memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease. The overall goal of this proposal is to define the mechanism(s) of how RSV-specific memory CD8 T cells inhibit CD4 T cell-mediated RSV vaccine-enhanced disease and immunopathology. We propose the following Specific Aims: 1) To determine the how memory CD8 T cells inhibit RSV-specific memory Th2 cells and RSV vaccine-enhanced pulmonary eosinophilia and, 2) To determine if memory CD8 T cells can prevent FI-RSV vaccine-enhanced disease and pulmonary injury. The underlying mechanisms of RSV vaccine-enhanced disease remain unclear. The studies in this proposal are designed to determine the role of RSV-specific memory CD8 T cells in decreasing the severity of CD4 T cell-mediated immunopathology in a model system with direct relevance to human disease.